Papers of the Month
By Sara Amolegbe
New database facilitates nanomaterial research
NIEHS grantees constructed PubVINAS, a large database of structure, chemical property, and activity information on 705 nanomaterials, covering 11 material types. With extensive data on each material, the publicly available database allows scientists to use the structures of new nanomaterials to predict their critical properties and potential toxicity.
Modern nanotechnology research has generated numerous experimental data for various nanomaterials. However, few nanomaterial databases have enough detail to be suitable for creating the complex mathematical models that predict behavior. The researchers built a database with nanostructure annotation, which is a computer-friendly format for encoding information about the structure of each nanomaterial. PubVINAS draws upon thousands of scientific papers and contains 705 unique nanomaterials, 1,365 physicochemical properties of those materials, and 2,386 data points related to their bioactivity, including whether the nanomaterials can be taken up by cells and lead to cell death. The nanostructures are stored as data files that can be downloaded by researchers worldwide.
Increased production, use, and environmental accumulation of nanomaterials present important concerns about potential health effects of new nanomaterials. According to the authors, the predictive models developed from this database can help researchers design and prioritize development of safer nanomaterials.
Citation: Yan X, Sedykh A, Wang W, Yan B, Zhu H. 2020. Construction of a web-based nanomaterial database by big data curation and modeling friendly nanostructure annotations. Nat Commun 11:2519.
Microglial exosomes linked to Parkinson's disease
NIEHS grantees found that microglia, the main resident immune cells in the brain, are involved in cell-to-cell transmission of the protein alpha-synuclein through the release of exosomes, which are small membrane-bound structures secreted by cells. Accumulation of alpha-synuclein in the brain is a prominent feature in Parkinson’s disease, a disorder of the central nervous system.
Neurons are fundamental cells of the brain and nervous system. When researchers treated neurons with alpha-synuclein, they observed that the protein was packaged into exosomes and released by microglia, triggering protein aggregation. When exosomes were combined with microglial proinflammatory cytokines, which are small proteins secreted by immune cells, these exosomes further increased alpha-synuclein aggregation in neurons.
Next, the researchers found that in mice, a single injection of synthetic alpha-synuclein was followed by cell-to-cell transmission of alpha-synuclein and abnormal aggregation in the mouse brain. By depleting microglia in the mice, the team was able to drastically suppress alpha-synuclein transmission. The researchers also purified microglia-derived exosomes from Parkinson’s disease patients and confirmed that they contained alpha-synuclein. In the lab, the patients’ microglial exosomes were capable of inducing alpha-synuclein aggregation in human neurons.
According to the authors, the study supports the view that microglial exosomes contribute to the progression of alpha-synuclein accumulation and therefore, they may serve as a promising therapeutic target for Parkinson’s disease.
Citation: Guo M, Wang J, Zhao Y, Feng Y, Han S, Dong Q, Cui M, Tieu K. 2020. Microglial exosomes facilitate alpha-synuclein transmission in Parkinson’s disease. Brain 143(5):1476–1497.
How traffic-related air pollution may affect brain development
Early-life exposure to traffic-related air pollution (TRAP) impaired brain development in rats, according to an NIEHS-funded study. Studies in human populations have linked TRAP to increased risk for various neurodevelopmental disorders, but there is limited evidence for a causal relationship between TRAP and adverse neurodevelopment.
To assess real-world TRAP exposures, the researchers exposed male and female rats during gestation and early postnatal development to TRAP drawn directly from a traffic tunnel in Northern California, delivering it unchanged and in real time to an exposure chamber. They compared neurodevelopmental outcomes in TRAP-exposed rats with animals exposed to filtered air.
In male rats, TRAP exposure increased expression of the protein doublecortin, which is used as an indicator of production of new neurons in the brain. TRAP-exposed male rats also had a higher percentage of cycling neural cells than unexposed rats in a region of the brain hippocampus where adult neuron production occurs. Compared with unexposed females, researchers observed that exposed female rats exhibited decreased volume of the lateral ventricles — the largest brain cavities containing cerebrospinal fluid — and increased layer width of small neurons found in the cerebellum called granule cells. These altered patterns of cellular growth and neuron production in both males and females are common in various neurodevelopmental disorders and intellectual disabilities.
According to the authors, the findings suggest that exposure to real-world levels of TRAP during gestation and early postnatal development modulate neurodevelopment. Their findings corroborate epidemiological evidence of an association between TRAP exposure and increased risk of neurodevelopmental disorders.
Citation: Patten KT, González EA, Valenzuela A, Berg E, Wallis C, Garbow JR, Silverman JL, Bein KJ, Wexler AS, Lein PJ. 2020. Effects of early life exposure to traffic-related air pollution on brain development in juvenile Sprague-Dawley rats. Transl Psychiatry 10(1):166.
Flame retardants may affect future generations via changes in sperm
NIEHS grantees reported that exposure to polybrominated biphenyl (PBB) 153, a type of brominated flame retardant, alters DNA methylation in sperm. DNA methylation refers to heritable changes in gene expression that occur with no alteration to the DNA sequence. PBB153 is known to be toxic to those who are directly exposed. The new study indicates that exposure may also harm future generations.
In 1973, a chemical company that manufactured both a brominated flame retardant and a nutritional supplement mistakenly shipped hundreds of pounds of the flame retardant, instead of the nutritional supplement, to grain mills around Michigan. The flame retardant was incorporated into animal feed, which introduced it into the food chain. As a result, an estimated 6.5 million Michigan residents consumed PBB-contaminated animal products.
The researchers found that circulating levels of PBB153, the primary component of the brominated flame retardant, were associated with methylation of genes in the sperm of men involved in a Michigan PBB study. Based on this information, they studied sperm in the lab and found that exposure to PBB153 decreased methylation at regions of DNA that control imprinted genes, which are essential for fetal growth and play an important role in other aspects of development.
According to the authors, the effects of PBB on epigenetic regulation in sperm may lead to developmental effects in offspring, which could explain some of the endocrine-related health effects that have been observed among children of PBB-exposed parents.
Citation: Greeson KW, Fowler KL, Estave PM, Thompson SK, Wagner C, Edenfield RC, Symosko KM, Steves AN, Marder EM, Terrell ML, Barton H, Koval M, Marcus M, Easley CA 4th. 2020. Detrimental effects of flame retardant, PBB153, exposure on sperm and future generations. Sci Rep 10(1):8567.
(Sara Amolegbe is a research and communication specialist for MDB Inc., a contractor for the NIEHS Division of Extramural Research and Training.)